Identifying novel treatments for resistant depression (TRD) is urgently needed to help improve the standard of care. To date, several preliminary studies have examined the use of atypical antipsychotic agents as adjuncts to standard antidepressants for TRD. However, the efficacy of this popular off-label treatment strategy has yet to be firmly established, while very little is known regarding the long-term effects (in terms of efficacy, tolerability and safety) of this treatment strategy. The atypical antipsychotic agent ziprasidone, in particular, may offer a unique opportunity to study as an adjunct for TRD for two principal reasons: I) its unique receptor-affinity profile, and, II) its favorable side-effect profile compared to the other agents in the class. Unfortunately, however, double-blind, placebo controlled trials of ziprasidone augmentation for TRD have not been conducted to date. If safe and effective as an antidepressant adjunct, ziprasidone would represent an attractive option for many of these patients who have had unsatisfactory initial response to standard treatment. If not found to be either safe or effective, the results of this proposed trial would also be highly informative given the significant proportion of TRD patients who, despite the relative paucity of data from independently-funded studies of rigorous design, are prescribed atypical antipsychotic agents off-label. The proposed study involves three phases. The first phase is an 8-week, open-label trial of an SSRI for MDD. Patients who do not experience sufficient symptom improvement following this open-label trial will be enrolled in an 8-week, double-blind, placebo controlled trial of ziprasidone augmentation (phase 2). Ziprasidone and placebo-remitters will then enter a 12-month, double-blind, extension phase (phase 3). The purpose of our study is to evaluate the efficacy, safety and tolerability of ziprasidone (20- 80mg twice-daily; flexible dose) as an adjunctive treatment in SSRI-resistant MDD. Secondary aims include: I) to determine whether ziprasidone augmentation is effective in relieving co-morbid anxious and painful symptoms of depression, and, II) to obtain preliminary data on the long-term safety and efficacy of adjunct ziprasidone. The study involves the enrollment of a total of 400 patients with MDD over the course of 5 years at either the Massachusetts General Hospital or the outpatient clinic of the department of Psychiatry at the Vanderbilt University School of Medicine. We estimate that 180 of these patients will enter the double-blind phase. [unreadable] [unreadable] [unreadable]